Low accuracy of the national reporting system of acute hepatitis C infection in Taiwan, 1995–2004

Background and Aim: This study attempted to clarify accuracy of acute hepatitis C (AHC) and its clinical characteristics. Methods: We reviewed 632 reported cases from national surveillance data of the Taiwan Center for Disease Control between 1995 and 2004, and reclassified diagnoses. A definite case was defined as alanine aminotransferase (ALT) > 10 × the upper limit of normal (ULN) with seroconversion of anti‐hepatitis C virus antibody (anti‐HCV). A probable case was defined as (i) seroconversion of anti‐HCV and/or elevated ALT levels; or (ii) anti‐HCV(+) but titers increased (from < 40 S/CO to ≥ 40 S/CO) and ALT > 10 × the ULN. A suspected case was defined as initial anti‐HCV(+) and ALT level > 10 × the ULN and/or jaundice. Excluded cases were defined as ALT levels less than 10 × ULN with initial positive anti‐HCV Ab. Results: A total of 310 (49%) cases were confirmed as AHC; these included 95 (15%) definite and 215 (34%) probable cases. Higher incidence rates and accuracy of AHC were demonstrated in the southern area significantly if compared with northern, eastern and central areas, respectively (all P < 0.05). On comparison between blood centers and hospitals, more AHC cases were found in Southern Taiwan than in other areas (157/73 vs 24/40, P < 0.001), younger mean age (33.3 ± 11.1 vs 49.3 ± 16.4, P < 0.001), lower ALT levels (263.1 ± 200.9 vs 1264.2 ± 706.8, P < 0.001) and male predominance (191/39 vs 46/18, P = 0.046). Conclusions: This study showed our reporting system over‐estimated the AHC diagnosis, which is also a common issue worldwide. Greater efforts are needed to establish appropriate reporting systems, as well as more supplemental methods to distinguish between prevalent and incident cases.     

Optimal treatment increased survival of hepatocellular carcinoma patients detected with community‐based screening

Background and Aim: The early detection of hepatocellular carcinoma (HCC) and opportunity to select appropriate treatment are important benefits of HCC screening. Our aim in the present study was to investigate the survival rate, prognostic factors and treatment effects in HCC patients of community‐based screening. Methods: Community‐based ultrasound (US) screening for HCC in adults with platelet counts (< 150 × 10³/mm³) and/or alpha fetoprotein (AFP) > 20 ng/mL was conducted in 2002 and 2004. As per the Barcelona Clinic Liver Cancer (BCLC) stage, 90 cases of intermediate or earlier stage HCC were detected and 88 cases had sufficient information for analysis (49 men and 39 women, aged 65.8 ± 9.6 years). The tumor diameter was mostly less than 5 cm (76.1%). The follow up was continued until June 2008. Results: The 4‐year overall survival rate was 46.8%. Old age (≥ 70 years) (P = 0.046), later stage of HCC (intermediate vs earlier) (P = 0.012), low platelet count (< 100 × 10³/mm³) (P = 0.013) and refusal of modern treatment (P = 0.026) were independent poor prognostic factors. Curative treatment increased survival in patients of all ages. Both curative treatment and transcatheter arterial embolization (TAE) increased survival in cases of intermediate HCC. However, treatment benefits were not found for patients with (very) early stage HCC. Conclusions: Early detection and prompt treatment of HCC leads to increased survival. For elderly patients this benefit was seen only for early stage cases receiving curative treatment. Differences between treatment types for patients with (very) early stage HCC might emerge with a longer follow‐up period.     

A randomized prospective comparison of chemotherapy to total body irradiation as initial treatment for the indolent lymphoproliferative diseases

One hundred eight consecutive patients with indolent lymphoproliferative diseases were stratified into chronic lymphocytic leukemia (CLL), stage III and IV well-differentiated lymphocytic lymphoma (WDLL), and stage III and IV follicular lymphoma (FL). Within each stratum, patients were prospectively and randomly assigned to receive chemotherapy with chlorambucil and prednisone (CP) or fractionated total body irradiation (TBI). Morbidity from both regimens was negligible. Complete response (CR) was defined as the resolution of organ enlargement and the return of blood count to normal. The CR rate for the entire CP group (n = 54) was 59% and that for the TBI group (n = 54), 52%; median survivals were 53 and 57 months respectively. In the 41 patients with CLL the CR rate for CP (n = 17) was 47% and that for TBI (n = 24), 50%; the median survival for CP was 48 months, and for TBI it was 51 months. In the 21 patients with WDLL the CR rate for CP (n = 15) was 53% and that for TBI (n = 6), 67%; the median survival for CP was 42 months and has not yet been reached for TBI. For the 46 patients with FL the CR rate for CP (n = 22) was 72% and that for TBI (n = 24), 50%; the median survival was 55 months, and for TBI it was 56 months. None of the differences in CR or survival are statistically significant (P greater than .05). In these indolent lymphoproliferative diseases, CP and TBI are equally effective forms of initial treatment irrespective of the end point being defined as CR or survival.     

Engraftment of bone marrow cells into normal unprepared hosts: effects of 5-fluorouracil and cell cycle status

Bone marrow from animals treated with 5-fluorouracil (5FU) competes equally with normal marrow when assessed in vivo in an irradiated mouse, but shows markedly defective engraftment when transplanted into noncytoablated hosts. Using Southern Blot analysis and a Y-chromosome specific probe, we determined the level of engraftment of male donor cells in the bone marrow, spleen, and thymus of unprepared female hosts. We have confirmed the defective engraftment of marrow harvested 6 days after 5FU (FU-6) and transplanted into unprepared hosts and shown that this defect is transient; by 35 days after 5FU (FU-35), engraftment has returned to levels seen with normal marrow. FU-6 marrow represents an actively cycling population of stem cells, and we hypothesize that the cycle status of the stem cell may relate to its capacity to engraft in the nonirradiated host. Accordingly, we have evaluated the cycle status of engrafting normal and FU-6 marrow into normal hosts using an in vivo hydroxyurea technique. We have shown that those cells engrafting from normal marrow and over 70% of the cells engrafting from FU-6 marrow were quiescent, demonstrating no killing with hydroxyurea. We have also used fluorescent in situ hybridization (FISH) analysis with a Y-chromosome probe and demonstrated that normal and post-5FU engraftment patterns in peripheral blood were similar to those seen in bone marrow, spleen, and thymus. Altogether these data indicate that cells engrafting in normal, unprepared hosts are dormant, and the defect that occurs after 5FU is concomitant with the induction of these cells to transit the cell cycle.     

The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism

BACKGROUND: The resistance of thrombi to fibrinolysis induced by plasminogen activators remains a major impediment to the successful treatment of thrombotic diseases. This study examines the contribution of activated factor XIII (factor XIIIa) to fibrinolytic resistance in experimental pulmonary embolism. METHODS AND RESULTS: The fibrinolytic effects of specific inhibitors of factor XIIIa-mediated fibrin-fibrin cross-linking and alpha2-antiplasmin-fibrin cross-linking were measured in anesthetized ferrets with pulmonary emboli. Five experimental groups were treated with heparin (100 U/kg) and/or tissue plasminogen activator (TPA, 1 mg/kg) and the percent (mean+/-SD) lysis of emboli was determined: (1) control, normal factor XIIIa activity (14.1+/-4. 8% lysis); (2) inhibited factor XIIIa activity (42.7+/-7.4%); (3) normal factor XIIIa activity+TPA (32.3+/-7.7%); (4) inhibited factor XIIIa activity+TPA (76.0+/-11.9%); and (5) inhibited alpha2-antiplasmin-fibrin cross-linking+TPA (54.7+/-3.9%). Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P<0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P<0.05). Among groups receiving TPA, selective inhibition of factor XIII-mediated alpha2-antiplasmin-fibrin cross-linking enhanced lysis (group 3 versus 5; P<0.0005). Complete inhibition of factor XIIIa also amplified lysis (group 3 versus 4; P<0.0001) and had greater effects than inhibition of alpha2-antiplasmin cross-linking alone (group 4 versus 5; P<0.0005). No significant fibrinogen degradation occurred in any group. CONCLUSIONS: Factor XIIIa-mediated fibrin-fibrin and alpha2-antiplasmin-fibrin cross-linking both caused experimental pulmonary emboli to resist endogenous and TPA-induced fibrinolysis. This suggests that factor XIIIa may play a critical role in regulating fibrinolysis in human thrombosis.     

Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells

The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth- factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence. In these p210 bcr-abl-transformed cells (H7 bcr-abl.A54) and in two other murine myeloid cell lines transformed to IL-3 independence by p210 bcr-abl, endogenous p21 RAS is activated as determined by an elevated ratio of associated guanosine triphosphate (GTP)/guanosine diphosphate (GDP), assayed by thin-layer chromatography of the nucleotides eluted from p21 RAS after immunoprecipitation with the Y13-259 antibody. Treatment of p210 bcr-abl-transformed cells with a specific tyrosine kinase inhibitor herbimycin A resulted in diminished tyrosine phosphorylation of p210 bcr-abl and associated proteins, without major reduction in expression of the p210 bcr-abl protein itself. Inhibition of p210 bcr-abl-dependent tyrosine phosphorylation resulted in a reduction of active p21RAS-GTP complexes in the transformed cells, in diminished expression of the nuclear early response genes c-jun and c-fos, and in lower cellular proliferation rate. To further implicate p21 RAS in these functional events downstream of p210 bcr-abl tyrosine phosphorylation, we targeted G- protein function directly by limiting the availability of GTP with the inosine monophosphate dehydrogenase inhibitor, tiazofurin (TR). In p210 bcr-abl-transformed cells treated for 4 hours with TR, in which the levels of GTP were reduced by 50%, but GDP, guanosine monophosphate, and adenosine triphosphate (ATP) were unaffected, p210 bcr-abl tyrosine phosphorylation was at control levels. However, expression of c-fos and c-jun nuclear proto-oncogenes were strongly inhibited and p21 RAS activity was downregulated. These findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS. Furthermore, p21 RAS activity is linked to pathways that regulate c-jun and c-fos expression.     

9‐month results of polymer‐free sirolimus eluting stents in young patients compared to a septuagenarian and octogenarian all‐comer population

Objectives

To evaluate the 9‐month safety and efficacy of polymer‐free sirolimus eluting drug eluting stents in septuagenarians and octogenarians.

Methods

An all‐comer, worldwide single armed trial ( ClinicalTrials.gov Identifier NCT02629575) was conducted to demonstrate the safety and efficacy of an ultra‐thin strut, polymer‐free sirolimus eluting stent (PF‐SES). The primary endpoint was the 9‐month target revascularization rate (TLR). Secondary endpoints included the rates of major adverse cardiac events (MACE), stent thrombosis (ST) and bleeding (BARC) in septuagenarians (≥70 years, <80 years), and in octogenarians (≥80 years) to be compared to the younger patient group (<70 years).

Results

A total of 1607 patients were treated with PF‐SES in the sub‐70‐year‐old age group, 694 in septuagenarians, and 371 in the octogenarian patient group. At 9 months, the MACE rates were 7.2% in octogenarians, 5.3% in septuagenarians, and 3.0% in the younger patient group (P = 0.001). These were mostly driven by all‐cause mortality (4.4% vs 1.9% vs 0.6%, P < 0.001) while the TLR rates were only numerically lower in the younger age group (P = 0.080). BARC 1‐5 bleeding events were more frequent in the older age group (1.9% vs 2.7% vs 4.6%, P = 0.012) whereas the rates for ST were not different (0.7% vs 0.6% vs 0.6%, P = 0.970).

Conclusions

In octogenarians treated with PF‐SES, the rates for MACE, overall mortality, and bleeding are higher as compared to the younger age groups. However, the rates for TLR and ST were not significantly different across the investigated age groups. PF‐SES are safe and effective in octogenarians.

     

High-resolution computed tomography in patients with atypical ‘cardiac‘ chest pain: a study investigating patients at 10-year cardiovascular risks defined by the Framingham and PROCAM scores

Background and objective Atypical ‘cardiac‘ chest pain (ACCP) is not usually caused by myocardial ischaemia. Current noninvasive investigations for these symptoms are not yet as accurate as invasive coronary angiography. The latest 64-row multi-detector computed tomography (MDCT) technology is non-invasive, has high specificity and negative predictive values for the detection of significant coronary disease. Our aim was to investigate if this modality can provide more information in the assessment of outpatients with ACCP in addition to established cardiovascular risk scores. Methods Seventy consecutive patients presenting to the outpatient clinic with ACCP underwent 64-row MDCT scan of the coronary arteries. They were categorized into low, medium or high risk groups based upon the Framingham and PROCAM scores. We defined a clinically abnormal MDCT scan as coronary stenosis =50% or calcium score ＞400 Agatston. Results Fifty-three (75.7%) patients did not have clinically abnormal scans. Framingham score classified 43 patients as low-risk while PROCAM classified 59 patients as low-risk. MDCT scans were abnormal for 18.6% and 22.0% of the respective low-risk group of patients. For patients with medium-to-high risk, 33.3% and 36.4% of Framingham and PROCAM patient groups respectively had abnormal MDCT scans. Conclusion MDCT adds valuable information in the assessment of patients with ACCP by identifying a significant proportion of patients categorized as low-risk to have underlying significant coronary stenosis and coronary calcification by established cardiovascular risk scores.